DE69015919T2 - 4- (2-methyl-2-hydrooxypropylamino) -5,6-dihydrothieno (2,3-B) thiopyran-2-sulfonamide-7,7-dioxide. - Google Patents

Description

SUMMARY OF THE INVENTION

The invention relates to a new compound of the structural formula:

and the pharmaceutically and ophthalinologically acceptable salts thereof. The invention further relates to pharmaceutical preparations and their use for systemic application and for application to the eye, wherein the new compound according to the invention is used as an active ingredient to prepare a medicament for treating increased intraocular pressure, especially when it is accompanied by pathological damage, as in the disease known as glaucoma.

BACKGROUND OF THE INVENTION

Glaucoma is an eye disorder characterized by elevated intraocular pressures that are too high for normal function and can lead to irreversible loss of vision. If left untreated, glaucoma can lead to blindness. Many ophthalmologists currently believe that ocular hypertension, the condition of elevated intraocular pressure without damage to the optic nerve head or without the characteristic glaucomatous visual field defects, represents the earliest stage of glaucoma. Many of the drugs used to date to treat glaucoma have not proved entirely satisfactory. In fact, little progress has been made in the treatment of glaucoma since the introduction of pilocarpine and physostigmine. Only recently have clinicians noticed that many adrenergic beta-blockers are effective in reducing intraocular pressure. Although many of these agents are effective in reducing intraocular pressure, they also have other properties, such as membrane-stabilizing activity, which are unacceptable for chronic ocular use. It has been found that (S)-1-tert-butylamino-[(4-morpholino-1,2,5-thiadiazol-3-yl)-oxy]-2-propanol, an adrenergic beta-blocker, reduces intraocular pressure and lacks many of the undesirable side effects associated with pilocarpine and also has advantages over many adrenergic beta-blockers, such as lacking local anesthetic properties, having a long duration of action and minimal tolerance.

Although pilocarpine, physostigmine and the above-mentioned beta-blockers reduce intraocular pressure, none of these drugs act by inhibiting the enzyme carbonic anhydrase and therefore by inhibiting the contribution to the formation of aqueous humor generated by the carbonic anhydrase pathway.

Agents called carbonic anhydrase inhibitors block or inhibit this pathway of inflow by inhibiting the enzyme carbonic anhydrase. While such carbonic anhydrase inhibitors are currently used to treat intraocular pressure by oral, intravenous, or other systemic routes, they have the distinct disadvantage of carbonic anhydrase inhibition throughout the body. Such large-scale disruption of a fundamental enzyme system is only justified during an acute attack of alarmingly elevated intraocular pressure or when no other agent is effective. Although it is desirable to direct the carbonic anhydrase inhibitor only to the desired target tissue in the eye, no topically effective carbonic anhydrase inhibitors are available for clinical use.

However, topically active carbonic anhydrase inhibitors are mentioned in U.S. Patents 4,386,098, 4,416,890 and 4,426,388. The compounds described here are 5-(and 6)-hydroxy-2-benzothiazolesulfonamides and the acyl esters thereof.

U.S. Patent Nos. 4,677,115 and 4,797,413 and U.S. Application Serial No. 17905, filed concurrently herewith, describe topically active carbonic anhydrase inhibitors that are also thieno[2,3-b]thiopyran-2-sulfonamides.

DETAILED DESCRIPTION OF THE INVENTION

The new compound according to the invention has the structural formula:

or a pharmaceutically acceptable salt thereof.

The new compound of the invention was originally isolated from rat urine and erythrocytes after a continuous oral dose with the compound of the formula:

at dose levels of 50 and 100 mg/kg/day. The compound was isolated from the biological matrix by selective solvent extraction under alkaline conditions and purified by repeated HPLC techniques using different mobile phase conditions. The structure of the metabolite was tentatively assigned based on derivatization reactions, chromatographic properties and NMR analyses as well as MS analyses. Unequivocal structural evidence was obtained by comparing the above properties with those of the subsequently synthesized material (vide infra). Further studies using a homochiral reagent demonstrated that the predominant enantiomer composition of the metabolite in the erythrocytes had the (+) configuration. In addition, this metabolite has also been isolated and quantitatively detected in the urine of rhesus monkeys and in the erythrocytes after single and multiple doses at doses of 2, 15 and 100 mg/kg/day.

The compound is synthesized by treating the unsubstituted amine with an isobutylene oxide in a lower alkanol such as methanol in a closed system at 60 to 70 ºC for about 18 hours.

The invention further relates to formulations suitable for topical administration to the eye in the form of solutions, gellable solutions, ointments, solid water-soluble inserts or gels suitable for treating glaucoma or other stages of increased intraocular pressure and containing about 0.1% to 15% by weight of the drug, in particular about 0.5 to 2% by weight of the drug, the remainder consisting of carriers and other excipients well known in the art.

The medicament in the new topical ophthalmic formulation comprises the new compound of the invention either alone or in combination with an adrenergic beta-blocker such as timolol maleate or with a parasympathomimetic such as pilocarpine. In such combinations the two active agents are present in approximately equal amounts.

Such a drug is suitable for the treatment of increased intraocular pressure. A major concern is treatment by topical ocular administration of about 0.1 to 25 mg, and especially 0.2 to 10 mg, of such a compound per day either in a single dose or on a schedule of 2 to 4 doses per day.

EXAMPLE 1 Preparation of 4-(2-methyl-2-hydroxypropylamino)-5,6- dihydrothieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide hydrochloride

A suspension of racemic 4-amino-5,6-dihydrothieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide (1.129 g, 4.0 mmol) in methanol (10 mL) containing isobutylene oxide (2.5 mL, 30 mmol) was sealed in a screw-cap tube and heated at 60-80 °C for 18 h. The cooled suspension was filtered to give the nearly pure product (1.2 g). This material was chromatographed on silica gel and separated by gradient elution with 10-15% methanol/chloroform containing 1% ammonium hydroxide. The purified product (948 mg) was suspended in ethanol (10 mL) and treated with excess ethanolic HCl. The suspension was warmed to give a clear solution. On cooling, the racemic hydrochloride salt (987 mg, 63% yield) crystallized, mp 227-228 ºC, decomposition.

Analysis calculated for C₁₁H₁₈N₂O₅S₃ HCl: N-7.17, C-33.79, H-4.90. Found: N-7.04, C-33.91, H-4.98. EXAMPLE 2 active ingredient monobasic sodium phosphate 2H₂O dibasic sodium phosphate 12H₂O benzalkonium chloride water for injection qs and.

The new compound, phosphate buffer salts and benzalkonium chloride are added to water and dissolved. The pH of the mixture is adjusted to 6.8 and diluted to volume. The mixture is sterilized by ionizing radiation.

EXAMPLE 3

active ingredient 5 mg

Petrolatum q.s. and. 1 g

The compound and petrolatum are mixed aseptically.

EXAMPLE 4

active ingredient 1 mg

Hydroxypropylcellulose q.s. 12mg

Ocular inserts are made from compression-molded films made on a Carver press by subjecting the powdered mixture of the above ingredients to a compressive force of 5,442 kg (12,000 lbs) (gauge pressure) at 149 ºC (300 ºF) for 1-4 minutes.

The film is cooled under pressure by circulating cold water in the plates. The eye inserts are then cut out of the film individually using a rod-shaped punch. Each insert is placed in a tube, which is then placed in a humidity chamber (88% R.H. at 30ºC) for 2 to 4 days. Upon removal from the humidity chamber, the tubes are stoppered and then capped. The tubes containing the hydrated insert are then autoclaved at 121ºC (250ºF) for 1/2 hour.

Claims (3)

1. Compound structural formula: 2. An ophthalmic formulation for treating ocular hypertension comprising an ophthalmologically acceptable carrier and an effective ocular antihypertensive amount of a compound according to claim 1. 3. Use of the compound according to claim 1 for the manufacture of a medicament suitable for the treatment of increased intraocular pressure.